Monoamine Oxidase-B Inhibitor Reduction in Pro-Inflammatory Cytokines Mediated by Inhibition of cAMP-PKA/EPAC Signaling
Mucosal epithelial cell integrity is an important component of innate immunity and it protects the host from an environment rich in microorganisms. Virulence factors from Gram-negative bacteria [e.g. lipopolysaccharide (LPS)] induce significant pro-inflammatory cytokine expression. Monoamine oxidase...
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| Autores principales: | , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Frontiers Media S.A.
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/a3437439d7814df39575ec0c56ff20e9 |
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| Sumario: | Mucosal epithelial cell integrity is an important component of innate immunity and it protects the host from an environment rich in microorganisms. Virulence factors from Gram-negative bacteria [e.g. lipopolysaccharide (LPS)] induce significant pro-inflammatory cytokine expression. Monoamine oxidase (MAO) inhibitors reduce cytokine expression in a variety of inflammatory models and may therefore have therapeutic potential for a number of inflammatory diseases. We tested the anti-inflammatory therapeutic potential of a recently developed reversible MAO-B inhibitor (RG0216) with reduced transport across the blood–brain barrier. In an epithelial cell culture model, RG0216 significantly decreased LPS-induced interleukin (IL)-6 and IL-1β gene and protein expression and was as effective as equimolar concentrations of deprenyl (an existing irreversible MAO-B inhibitor). Hydrogen peroxide and modulating dopamine receptor signaling had no effect on cytokine expression. We showed that LPS-induced expression of IL-6 and IL-1β was cAMP dependent, that IL-6 and IL-1β expression were induced by direct cAMP activation (forskolin) and that RG0216 and deprenyl effectively reduced cAMP-mediated cytokine expression. Targeted protein kinase A (PKA) and Exchange Protein Activated by cAMP (EPAC) activation regulated IL-6 and IL-1β expression, albeit in different ways, but both cytokines were effectively decreased with RG0216. RG0216 reduction of LPS-induced cytokine expression occurred by acting downstream of the cAMP-PKA/EPAC signaling cascade. This represents a novel mechanism by which MAO-B selective inhibitors regulate LPS-induced IL-6 and IL-1β expression. |
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